Beamion BCGC-1: A Phase Ib Dose Escalation and Phase II Dose Optimization, Randomized, Open-label, Multicenter Trial of Oral Zongertinib (BI 1810631) Alone or in Combination With Other Agents for the Treatment of Patients With Advanced HER2+ Metastatic Breast Cancer (mBC), Metastatic Gastric, Gastroesophageal Junction, or Esophageal Adenocarcinoma (mGEAC), or Metastatic Colorectal Cancer (mCRC)
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 768
- 试验地点
- 188
- 主要终点
- Dose escalation (Phase Ib): Occurrence of dose-limiting toxicities (DLTs) in the maximum tolerated dose (MTD) evaluation period
研究概览
简要总结
This study is open to adults aged 18 years and older with different types of HER2+ cancer that has spread and cannot be removed by surgery. People can take part in this study if their tumours show HER2 aberrations and previous treatment was not successful. The purpose of this study is to find a suitable dose of zongertinib that people with different types of HER2+ cancer that has spread can tolerate best when taken together with trastuzumab deruxtecan (T-DXd), with trastuzumab emtansine (T-DM1), with trastuzumab and capecitabine, with zanidatamab, or with mFOLFOX6 (with or without trastuzumab). Another purpose is to check whether zongertinib alone and in combination with other treatments can make tumours shrink. Zongertinib inhibits HER2. HER2 causes cancer cells to grow.
In this study, participants receive treatment in cycles. Study participants are treated with zongertinib alone or in combination with other treatments. This study has 2 parts. In Part 1, participants in different groups receive increasing doses of zongertinib. In Part 2, participants are put into different groups by chance. Each group receives a different dose of zongertinib. Every participant has an equal chance of being in each group.
During the study, the participants visit the study site regularly. In this study, researchers want to find the highest dose of zongertinib that participants can tolerate when taken together with other treatments. To find this out, researchers look at certain severe health problems that a number of participants have. The doctors regularly check the size of the tumour with imaging methods (CT/MRI) during the study. The doctors also regularly check participants' health and take note of any unwanted effects.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients ≥18 years of age or over the legal age of consent in countries where that is greater than 18 years at the time of signature of the informed consent form (ICF)
- •Cohorts A to K and Cohort O: Documented Human epidermal growth factor receptor 2 overexpressing and/or amplified (HER2+), metastatic breast cancer (mBC) or metastatic gastric adenocarcinoma, gastroesophageal junction adenocarcinoma, or esophageal adenocarcinoma (mGEAC).
- •Cohorts L (L-ext), M, and N (metastatic colorectal cancer (mCRC)): Documented Human epidermal growth factor receptor 2 (HER2) overexpression/amplification according to American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) gastric cancer guidelines and according to the result of local testing.
- •For dose optimization and justification (Phase II): Patient must provide tumor tissue from locations not radiated prior to biopsy, if possible, collected through archival tissue
- •History of prior treatment lines in palliative setting:
- •For cohorts A, B, C, D, E, F, G, H, I, I-ext, J, J-ext, K and O documented investigator assessed progression after HER2-directed treatment for unresectable locally advanced or metastatic disease (For Cohorts D, H, I (I-ext), J (J-ext) - patients must have been pretreated with trastuzumab deruxtecan (T-DXd) and have progressed or have been intolerant to previous T-DXd).
- •For cohorts L, L-ext, M and N documented progression or recurrence of disease during or following their latest line of therapy. Patients must have had at least one prior line of therapy for locally advanced unresectable disease or metastatic disease (adjuvant and neoadjuvant therapy excluded) and documented disease progression or recurrence of disease during or following their latest line of therapy. In the opinion of the Investigator, patients must be unlikely to tolerate or derive clinically meaningful benefit from further standard of care therapy known to prolong survival.
- •Presence of at least one measurable lesion according to RECIST 1.1
- •Eastern Cooperative Oncology Group (ECOG) score of 0 or 1
- •Adequate organ function based on laboratory values Further inclusion criteria apply.
排除标准
- •Previous treatment with:
- •Any small molecule HER2 inhibitor in the palliative setting in Cohorts D, E, F, H, L, L-ext, M, and N. In Cohort D allowed in up to 15 patients in each dose level (DL).
- •T-DXd in Cohorts E and F. In Cohort E allowed in up to 15 patients in each DL.
- •trastuzumab emtansine (T-DM1) in the palliative setting in Cohort D and H. In Cohort H allowed in up to 15 patients in each DL.
- •Capecitabine in Cohort D and H. In Cohort D allowed in up to 15 patients in each DL
- •Presence of uncontrolled and/or symptomatic brain metastases, or leptomeningeal disease
- •Mean resting corrected QT interval (QT interval corrected for heart rate by Fridericia´s formula (QTcF)) >470 msec.
- •Any factors that increase the risk of QT interval corrected for heart rate (QTc) prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, personal or family history of long QT syndrome or unexplained sudden death under 40 years-of-age.
- •Ejection fraction <50% or the lower limit of normal of the institutional standard within 28 days prior to randomization
- •History of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids, current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening Further exclusion criteria apply.
研究组 & 干预措施
Phase Ib - Cohort N: zongertinib + trastuzumab + mFOLFOX6
Dose escalation (Phase Ib)
干预措施: mFOLFOX6 (Drug)
Phase Ib - Cohort M: zongertinib + mFOLFOX6
Dose escalation (Phase Ib)
干预措施: mFOLFOX6 (Drug)
Phase Ib - Cohort A: zongertinib + Trastuzumab emtansine
Dose escalation (Phase Ib)
干预措施: Trastuzumab emtansine (Drug)
Phase II - Cohort J-ext: zongertinib + trastuzumab
Extension Phase II
干预措施: Trastuzumab (Drug)
Phase Ib - Cohort N: zongertinib + trastuzumab + mFOLFOX6
Dose escalation (Phase Ib)
干预措施: Trastuzumab (Drug)
Phase II - Cohort D: zongertinib + Trastuzumab emtansine
Dose optimization (Phase II).
干预措施: Trastuzumab emtansine (Drug)
Phase II - Cohort I: zongertinib
Dose optimization (Phase II).
干预措施: Zongertinib (Drug)
Phase Ib - Cohort G: zongertinib + trastuzumab + capecitabine
Dose escalation (Phase Ib)
干预措施: Trastuzumab (Drug)
Phase II - Cohort J: zongertinib + trastuzumab
Dose optimization (Phase II).
干预措施: Trastuzumab (Drug)
Phase Ib - Cohort N: zongertinib + trastuzumab + mFOLFOX6
Dose escalation (Phase Ib)
干预措施: Zongertinib (Drug)
Phase II - Cohort J: zongertinib + trastuzumab
Dose optimization (Phase II).
干预措施: Zongertinib (Drug)
Phase II - Cohort D: zongertinib + Trastuzumab emtansine
Dose optimization (Phase II).
干预措施: Zongertinib (Drug)
Phase Ib - Cohort K: zongertinib + trastuzumab
Dose escalation (Phase Ib)
干预措施: Trastuzumab (Drug)
Phase Ib - Cohort O: zongertinib + zanidatamab
Dose escalation (Phase Ib) - is not conducted in China or South Korea
干预措施: zanidatamab (Drug)
Phase Ib - Cohort B: zongertinib + Trastuzumab deruxtecan
Dose escalation (Phase Ib)
干预措施: Trastuzumab deruxtecan (Drug)
Phase Ib - Cohort C: zongertinib + Trastuzumab deruxtecan
Dose escalation (Phase Ib)
干预措施: Zongertinib (Drug)
Phase Ib - Cohort M: zongertinib + mFOLFOX6
Dose escalation (Phase Ib)
干预措施: Zongertinib (Drug)
Phase II - Cohort E: zongertinib + Trastuzumab deruxtecan
Dose optimization (Phase II).
干预措施: Trastuzumab deruxtecan (Drug)
Phase II - Cohort E: zongertinib + Trastuzumab deruxtecan
Dose optimization (Phase II).
干预措施: Zongertinib (Drug)
Phase II - Cohort L: zongertinib + trastuzumab
Dose justification (Phase II)
干预措施: Trastuzumab (Drug)
Phase II - Cohort L-ext: zongertinib + trastuzumab
Extension Phase II
干预措施: Zongertinib (Drug)
Phase II - Cohort H: zongertinib + trastuzumab + capecitabine
Dose optimization (Phase II).
干预措施: Trastuzumab (Drug)
Phase II - Cohort F: zongertinib + Trastuzumab deruxtecan
Dose optimization (Phase II).
干预措施: Trastuzumab deruxtecan (Drug)
Phase II - Cohort F: zongertinib + Trastuzumab deruxtecan
Dose optimization (Phase II).
干预措施: Zongertinib (Drug)
Phase II - Cohort H: zongertinib + trastuzumab + capecitabine
Dose optimization (Phase II).
干预措施: Zongertinib (Drug)
Phase Ib - Cohort A: zongertinib + Trastuzumab emtansine
Dose escalation (Phase Ib)
干预措施: Zongertinib (Drug)
Phase II - Cohort H: zongertinib + trastuzumab + capecitabine
Dose optimization (Phase II).
干预措施: Capecitabine (Drug)
Phase II - Cohort L: zongertinib + trastuzumab
Dose justification (Phase II)
干预措施: Zongertinib (Drug)
Phase Ib - Cohort B: zongertinib + Trastuzumab deruxtecan
Dose escalation (Phase Ib)
干预措施: Zongertinib (Drug)
Phase II - Cohort L-ext: zongertinib + trastuzumab
Extension Phase II
干预措施: Trastuzumab (Drug)
Phase Ib - Cohort C: zongertinib + Trastuzumab deruxtecan
Dose escalation (Phase Ib)
干预措施: Trastuzumab deruxtecan (Drug)
Phase Ib - Cohort G: zongertinib + trastuzumab + capecitabine
Dose escalation (Phase Ib)
干预措施: Capecitabine (Drug)
Phase Ib - Cohort G: zongertinib + trastuzumab + capecitabine
Dose escalation (Phase Ib)
干预措施: Zongertinib (Drug)
Phase Ib - Cohort O: zongertinib + zanidatamab
Dose escalation (Phase Ib) - is not conducted in China or South Korea
干预措施: Zongertinib (Drug)
Phase Ib - Cohort K: zongertinib + trastuzumab
Dose escalation (Phase Ib)
干预措施: Zongertinib (Drug)
Phase II - Cohort I-ext: zongertinib
Extension Phase II
干预措施: Zongertinib (Drug)
Phase II - Cohort J-ext: zongertinib + trastuzumab
Extension Phase II
干预措施: Zongertinib (Drug)
结局指标
主要结局
Dose escalation (Phase Ib): Occurrence of dose-limiting toxicities (DLTs) in the maximum tolerated dose (MTD) evaluation period
时间窗: up to 21 days
The MTD evaluation period is defined as the first 21 days of the first treatment cycle for Cohorts A, B, C, G, K, and O. The MTD evaluation period is defined as the first 28 days after the first administration of any trial medication for Cohorts M and N.
Dose optimization and justification (Phase II): Objective response (OR)
时间窗: up to 50 months
Objective response (OR) is defined as the best overall response of confirmed complete response (CR) or confirmed partial response (PR) according to RECIST 1.1 from the date of treatment start until the earliest date of disease progression, death, or last evaluable tumor assessment before start of subsequent anti-cancer therapy, or treatment discontinuation as assessed by investigator review.
次要结局
- Dose escalation (Phase Ib): Objective response (OR)(up to 50 months)
- Dose escalation (Phase Ib): Occurrence of dose-limiting toxicities (DLTs) during the entire treatment period(up to 50 months)
- Dose escalation (Phase Ib): Objective response (OR)(up to 50 months)
- Dose escalation (Phase Ib): Occurrence of dose-limiting toxicities (DLTs) during the entire treatment period(up to 50 months)
- Dose escalation (Phase Ib): Maximum measured concentration of zongertinib (at steady state) (Cmax,(ss))(up to 2 days)
- Dose escalation (Phase Ib): Area under the concentration-time curve of zongertinib over the time interval from 0 to 4h at steady state (AUC0-4h,ss)(up to 2 days)
- Dose escalation (Phase Ib): Area under the concentration-time curve of zongertinib over the time interval from 0 to the last quantifiable data point at steady state (AUC0-tz,ss)(up to 2 days)
- Dose optimization and justification (Phase II): Progression-free survival (PFS)(up to 50 months)
- Dose optimization and justification (Phase II): Disease control (DC)(up to 50 months)
- Dose optimization and justification (Phase II): Occurrence of treatment-emergent AEs leading to zongertinib (BI 1810631) dose reduction during the on-treatment period(up to 50 months)
- Dose optimization and justification (Phase II): Maximum measured concentration (at steady state) (Cmax,(ss))(up to 50 months)
- Dose optimization and justification (Phase II): Area under the concentration-time curve over the time interval from 0 to the last quantifiable data point at steady state (AUC0-tz,ss)(up to 50 months)
- Dose optimization and justification (Phase II): Patient-reported outcome (PRO) - PRO-CTCAE(up to 24 weeks)
- Dose optimization and justification (Phase II): Patient-reported outcome (PRO) - EORTC IL46(up to 48 weeks)
- Dose optimization and justification (Phase II): Patient-reported outcome (PRO) - EORTC IL19(up to 48 weeks)